Alkylating Agents & Platinum Agents Flashcards
In what way do Alkyating Agents work?
- Creating electrophilic intermediates that react with nucleophiles on DNA
Within DNA, what is the most common site of Alkylation?
- Guanine N7
When it says that the most effective cancer drugs are “bifunctional”, what does that mean?
- There are two groups that get alkylated = inter or intra strands
- Also creates crosslinks
Why was mustard gas first used within medicine?
- Used as chemical warfare in WWI
- Doctors saw decrease in Lymph Nodes and Myleosuppression
- used in treatment for leukemia and lymphoma
What is the mechanism of action for the Nitrogen Mustard?
- Creates an aziridinium ion that is electrophilic, making it want to bind with the nucleophilic Guanine N7
What are the effects caused by the alkylation?
- It causes the inter [separate] and intra [same] strands that inhibit DNA replication
For Alkylating Agents, what phase of the cell cycle do they mainly affect?
- Non Cell cycles specific as they just damage all DNA agents
What are some of the side effects caused by the alkylating agents?.
- Nausea, Vomiting, Myleosuppression, Gut Mucosa = caused by the rapid DNA proliferation
- Monoadduct
What does it mean when the alkylating agents are monoadduct?
- Mutagenic, carinogenic, teratogenic
- Has the ability to develop a second tumor
What is Mechlorethamine?
- 1st Alkylating Agent that is VERY reactive
What are the side effects for ALL alkylating agents?
- Myleosuppression
- Nausea & Vomiting
- Carcinogenic & Teratogenic
Since Mechlorethemine is so reactive, what are TWO strategies that are used to reduce the reactivity
- Decrease nucleophiicity of Nitrogen by adding aryl groups
- Prodrug Strategy
How does adding the aryl group help with reducing reactivity?
- Adding an aryl group will make the pKa of the group to drop = decrease in nucleophile
What drugs within alkylating helps with creating those aryl groups decreaings the nucleophilicity?
- Chlorambucial
- Also Bendamustine & Melphalan
What is the drug that helps with the Prodrug Strategy within alkylating groups?
- Cyclophosphamide
What is the mechanism of action for Cyclophosphamide?
- Need P450 to hydroxlyate it creating the electrophilic compound and acrolein
What must Cyclophosphamide be converted to to actaully work?
- Phosphormaide Mustard
- Aldehyde Dehydrogenase is inactivated
What are some of the side effects for Cyclophosphamide?
- Mild Myelosuppression = ADH in bone
- Hemorrhagic Cyctitis
What causes the Hemorrhagic Cyctitis caused by using Cyclophosphamide?
- Acrolein = By Product
- Toxic toward the bladder since it accumulates in the urine
What is one way that we can treat/prevent hemorrhagic cystits from forming?
- Ussing Mesna = Contains charged sulfonate groups so it does not penetrate cells [accumulates in urine] binds to acrolein to inactivate it
What is the way that Platinum Drugs are used?
- Very similar as alkylating agents as they make crosslinks BUT they are NOT alkylating agents
What is the mechanism of action for the platinum drugs?
- Platinum complex where H20 will bind to the leaving groups creating an AQUO FORM.
- Aquo Form will then create those crosslinks with DNA
In what way does the Aquo Forms react with DNA?
- Intrastanded Crosslinks with Guanine N7 & Adenine N7
What is the main Platinum drug that is used in the class?
- Cisplatin
What is important to know about Cisplatin?
- Produces primarly Intrastrand Crosslinks from nonenzymatic conversion
- More sensitve in G1 than in S phase
What are some of the side effects of Cisplatin?
- Dose-Limiting Nephrotoxicitity
- Severe Nausea & Vomting
- Minimal Bone Marrow toxicit
- Peripheral Neuropathy
- Hearing loss
What are some drug resistance mechanisms for the platinum drugs?
- Increase in conc. of glutathione [VERY HIGH reactivity toward electrophilic]
- Increased expression of Glutathione S-Transferase [what catalyses it]
